Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

• Cancer an uncontrolled proliferation of cells, is a multifactorial disease characterized by tumor formation, growth, and in some instances, metastasis.
• Cells carrying an activated oncogene, damaged genome, or other cancer-promoting alterations can be prevented from replicating through an elaborate tumor suppression network.
• a central component of this tumor suppression network is p53, one of the most potent tumor suppressors in the cell. Both the wild type and mutant conformations of p53 are implicated in the progression of cancer.
• each is independently a single bond or a double bond
• X 5 is CR 13 , N, or NR 13 :
• X 1 , X 2 , X 3 , and X 4 is a carbon atom connected to Q ;
• n 1, 2, 3, or 4;
• Y is N, O, or absent
• R 1 is -C(0)R 16 , -C(0)OR 16 , -C(0)NR 16 R 17 , -OR 16 , -SR 16 , -NR 16 R 17 , - NR 16 C(0)R 16 , -OC(0)R 16 , -SiR 16 R 17 R 18 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen;
• each R 3 and R 4 is independently -C(0)R 19 , -C(0)OR 19 , -C(0)NR 19 R 20 , -SOR 19 , -SO 2 R 19 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, or R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are bound form a ring, wherein the ring is substituted or unsubstituted, or R 3 is absent; each R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 is independently -C(0)R 21 , -C(0)OR 21 , -C(0)NR 21 R 22 , -OR 21 , -SR 21 , -NR 21 R 22 ,
• each R 19 and R 20 is -C(0)R 23 , -C(0)OR 23 , -C(0)NR 23 R 24 , -OR 23 , -SR 23 , - NR 23 R 24 , -NR 23 C(0)R 24 , -OC(0)R 23 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
• each R 21 and R 22 is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen;
• each R 23 and R 24 is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen,
• the invention provides a method of increasing p53 mutant activity in a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound that binds the p53 mutant, wherein the compound increases the ability of the p53 mutant to bind DNA.
• the invention provides a method of inducing apoptosis in a cell, the method comprising contacting the cell with a therapeutically-effective amount of a compound that binds a p53 mutant, wherein the compound increases the ability of the p53 mutant to bind DNA, wherein the cell expresses the p53 mutant.
• the invention provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound that binds a p53 mutant in the subject, wherein the binding of the compound to the p53 mutant increases the ability of the p53 mutant to bind DNA as compared to the ability of the p53 mutant to bind DNA in absence of the compound.
• the invention provides a method of determining an ability of a compound to activate mutant p53 binding to DNA, the method comprising:
• control sample comprises the tagged mutant p53 moiety, the antibody conjugated to the fluorescence energy acceptor against the tag of the tagged mutant p53 moiety, the biotin-labeled DNA, and the streptavidin conjugated to the fluorescence energy donor, wherein the control sample does not comprise the compound;
• the invention provides a method of increasing p53 mutant activity in a cell, the method comprising contacting the cell with a therapeutically effective amount of a compound that binds the p53 mutant, wherein the compound increases the ability of the p53 mutant to bind DNA by at least about 50% in an assay, wherein the assay comprises:
• control sample comprises the tagged mutant p53 moiety, the antibody conjugated to the fluorescence energy acceptor against the tag of the tagged mutant p53 moiety, the biotin-labeled DNA, and the streptavidin conjugated to the fluorescence energy donor, wherein the control sample does not comprise the compound;
• the invention provides a method of inducing apoptosis in a cell, the method comprising contacting the cell with a therapeutically-effective amount of a compound that binds a p53 mutant, wherein the cell expresses the p53 mutant, wherein the compound increases the ability of the p53 mutant to bind DNA by at least about 50% in an assay, wherein the assay comprises:
• control sample comprises the tagged mutant p53 moiety, the antibody conjugated to the fluorescence energy acceptor against the tag of the tagged mutant p53 moiety, the biotin-labeled DNA, and the streptavidin conjugated to the fluorescence energy donor, wherein the control sample does not comprise the compound;
• the invention provides a method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically-effective amount of a compound that binds a p53 mutant in the subject, wherein the binding of the compound to the p53 mutant increases the ability of the p53 mutant to bind DNA by at least about 50% as compared to the ability of the p53 mutant to bind DNA in absence of the compound as determined by an assay, wherein the assay comprises:
• control sample comprises the tagged mutant p53 moiety, the antibody conjugated to the fluorescence energy acceptor against the tag of the tagged mutant p53 moiety, the biotin-labeled DNA, and the streptavidin conjugated to the fluorescence energy donor, wherein the control sample does not comprise the compound;
• FIGURE 1 shows a protein DNA binding assay of mutant p53 in the presence of compound of the invention.
• FIGURE 2 shows a protein DNA binding assay of mutant p53 in the presence of a compound of the invention to demonstrate the specificity of a compound of the invention.
• the present invention provides compounds and methods for restoring wild-type function to mutant p53.
• the compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA.
• the restoration of activity of the p53 mutant can allow for the activation of downstream effectors of p53 leading to inhibition of cancer progression.
• the invention further provides methods of treatment of a cancerous lesion or a tumor harboring a p53 mutation.
• Cancer is a collection of related diseases characterized by uncontrolled proliferation of cells with the potential to metastasize throughout the body. Cancer can be classified into five broad categories including, for example: carcinomas, which can arise from cells that cover internal and external parts of the body such as the lung, breast, and colon; sarcomas, which can arise from cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues; lymphomas, which can arise in the lymph nodes and immune system tissues; leukemia, which can arise in the bone marrow and accumulate in the bloodstream; and adenomas, which can arise in the thyroid, the pituitary gland, the adrenal gland, and other glandular tissues.
• carcinomas which can arise from cells that cover internal and external parts of the body such as the lung, breast, and colon
• sarcomas which can arise from cells that are located in bone, cartilage, fat, connective tissue, muscle, and other supportive tissues
• lymphomas which can arise in the lymph nodes and immune system tissues
• leukemia which can
• Cancer begins when a cell breaks free from the normal restraints on cell division and begins to grow and divide out of control. Genetic mutations in the cell can preclude the ability of the cell to repair damaged DNA or initiate apoptosis, and can result in uncontrolled growth and division of cells.
• Oncogenes and tumor suppressor genes can regulate the proliferation of cells. Genetic mutations can affect oncogenes and tumor suppressors, potentially activating or suppressing activity abnormally, further facilitating uncontrolled cell division. Whereas oncogenes assist in cellular growth, tumor suppressor genes slow cell division by repairing damaged DNA and activating apoptosis.
• Cellular oncogenes that can be mutated in cancer include, for example, Cdkl, Cdk2, Cdk3, Cdk4, Cdk6, EGFR, PDGFR, VEGF, HER2, Raf kinase, K-Ras, and myc.
• Tumor suppressor genes that can be mutated in cancer include, for example, BRCA1,
• BRCA2 cyclin-dependent kinase inhibitor 1C, Retinoblastoma protein (pRb), PTEN, pi 6, p27, p53, and p73.
• Tumor suppressor p53 Tumor suppressor p53
• the tumor suppressor protein p53 is a 393 amino acid transcription factor that can regulate cell growth in response to cellular stresses including, for example, UV radiation, hypoxia, oncogene activation, and DNA damage.
• p53 has various mechanisms for inhibiting the progression of cancer including, for example, initiation of apoptosis, maintenance of genomic stability, cell cycle arrest, induction of senescence, and inhibition of angiogenesis. Due to the critical role of p53 in tumor suppression, p53 is inactivated in almost all cancers either by direct mutation or through perturbation of associated signaling pathways involved in tumor suppression. Homozygous loss of the p53 gene occurs in almost all types of cancer, including carcinomas of the breast, colon, and lung. The presence of certain p53 mutations in several types of human cancer can correlate with less favorable patient prognosis.
• p53 levels are maintained at low levels via the interaction of p53 with Mdm2, an E3 ubiquitin ligase.
• Mdm2 can target p53 for degradation by the proteasome.
• the interaction between Mdm2 and p53 is disrupted, and p53 accumulates.
• the critical event leading to the activation of p53 is phosphorylation of the N-terminal domain of p53 by protein kinases, thereby transducing upstream stress signals.
• the phosphorylation of p53 leads to a conformational change, which can promote DNA binding by p53 and allow transcription of downstream effectors.
• p53 can induce, for example, the intrinsic apoptotic pathway, the extrinsic apoptotic pathway, cell cycle arrest, senescence, and DNA repair.
• p53 can activate proteins involved in the above pathways including, for example, Fas/Apol, KILLER/DR5, Bax, Puma, Noxa, Bid, caspase-3, caspase-6, caspase-7, caspase-8, caspase-9, and p21 (WAFl). Additionally, p53 can repress the transcription of a variety of genes including, for example, c-MYC, Cyclin B, VEGF, RAD51, and hTERT.
• Each chain of the p53 tetramer is composed of several functional domains including the transactivation domain (amino acids 1-100), the DNA-binding domain (amino acids 101- 306), and the tetramerization domain (amino acids 307-355), which are highly mobile and largely unstructured.
• Most p53 cancer mutations are located in the DNA-binding core domain of the protein, which contains a central / ⁇ -sandwich of anti-parallel / ⁇ -sheets that serves as a basic scaffold for the DNA-binding surface.
• the DNA-binding surface is composed of two ⁇ - turn loops, L2 and L3, which are stabilized by a zinc ion, for example, at Argl75 and Arg248, and a loop-sheet-helix motif.
• Mutations in p53 located in the DNA-binding domain of the protein or periphery of the DNA-binding surface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Vall43, Hisl68, Argl75, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282.
• p53 mutations that can abrogate the activity of p53 include, for example, R175H, Y220C, G245S, R248Q, R248W, R273H, and R282H. These p53 mutations can either distort the structure of the DNA-binding site or thermodynamically destabilize the folded protein at body temperature. Wild-type function of p53 mutants can be recovered by binding of the p53 mutant to a compound that can shift the folding-unfolding equilibrium towards the folded state, thereby reducing the rate of unfolding and destabilization.
• Non-limiting examples of amino acids include: alanine (A,Ala); arginine (R, Arg); asparagine (N, Asn); aspartic acid (D, Asp); cysteine (C, Cys); glutamic acid (E, Glu);
• glutamine Q, Gin
• glycine G, Gly
• histidine H, His
• isoleucine I, He
• leucine L, Leu
• lysine K, Lys
• methionine M, Met
• phenylalanine F, Phe
• proline P, Pro
• serine S, Ser
• threonine T, Thr
• tryptophan W, Trp
• tyrosine Y, Tyr
• valine V, Val
• the compounds of the present invention can selectively bind to a p53 mutant and can recover wild-type activity of the p53 mutant including, for example, DNA binding function and activation of downstream targets involved in tumor suppression.
• a compound of the invention selectively binds to the p53 Y220C mutant.
• the Y220C mutant is a temperature sensitive mutant, which binds to DNA at lower temperature and is denatured at body temperature.
• a compound of the invention can stabilize the Y220C mutant to reduce the likelihood of denaturation of the protein at body temperature.
• the aromatic ring of Y220 is an integral part of the hydrophobic core of the / ⁇ -sandwich.
• the Y220C mutation can be highly destabilizing, due to the formation of an internal surface cavity.
• a compound of the invention can bind to and occupy this surface crevice to stabilize the / ⁇ -sandwich, thereby restoring wild-type p53 DNA-binding activity.
• assays can be employed to detect, for example, a conformational change in the p53 mutant or activation of wild-type p53 targets.
• Conformational changes in p53 can be measured by, for example, differential scanning fluorimetry (DSF), isothermal titration calorimetry (ITC), nuclear magnetic resonance spectrometry (NMR), or X-ray
• antibodies specific for the wild type of mutant conformation of p53 can be used to detect a conformational change via, for example, immunoprecipitation (IP), immunofluorescence (IF), or immunoblotting.
• Methods used to detect the ability of the p53 mutant to bind DNA can include, for example, DNA affinity immunoblotting, modified enzyme-linked immunosorbent assay (ELISA), electrophoretic mobility shift assay (EMSA), fluorescence resonance energy transfer (FRET), homogeneous time-resolved fluorescence (HTRF), and a chromatin immunoprecipitation (ChIP) assay.
• ELISA modified enzyme-linked immunosorbent assay
• EMSA electrophoretic mobility shift assay
• FRET fluorescence resonance energy transfer
• HTRF homogeneous time-resolved fluorescence
• ChIP chromatin immunoprecipitation
• the activation of downstream targets in the p53 signaling cascade can be measured.
• Activation of p53 effector proteins can be detected by, for example, immunohistochemistry (IHC-P), reverse transcription polymerase chain reaction (RT-PCR), and western blotting.
• the activation of p53 can also be measured by the induction of apoptosis via the caspase cascade and using methods including, for example, Annexin V staining, TUNEL assays, pro-caspase and caspase levels, and cytochrome c levels.
• Another consequence of p53 activation is senescence, which can be measured using methods such as?-galactosidase staining.
• a p53 mutant that can be used to determine the effectiveness of a compound of the invention to increase the DNA binding ability of a p53 mutant is a p53 truncation mutant, which contains only amino acids 94-312, encompassing the DNA-binding domain of p53.
• the sequence of the p53 Y220C mutant used for testing compound efficacy can be:
• a compound of the invention can increase the ability of a p53 mutant to bind DNA by at least or up to about 0.1%, at least or up to about 0.2%, at least or up to about 0.3%>, at least or up to about 0.4%, at least or up to about 0.5%, at least or up to about 0.6%>, at least or up to about 0.7%), at least or up to about 0.8%>, at least or up to about 0.9%, at least or up to about 1%), at least or up to about 2%, at least or up to about 3%, at least or up to about 4%, at least or up to about 5%, at least or up to about 6%, at least or up to about 7%, at least or up to about 8%), at least or up to about 9%, at least or up to about 10%, at least or up to about 11%, at least or up to about 12%, at least or up to about 13%, at least or up to about 14%, at least or up to about 15%o, at least or up to about 16%, at least
• a compound described herein can increase the activity of the p53 mutant that is, for example, at least or up to about 2-fold, at least or up to about 3-fold, at least or up to about 4- fold, at least or up to about 5-fold, at least or up to about 6-fold, at least or up to about 7-fold, at least or up to about 8-fold, at least or up to about 9-fold, at least or up to about 10-fold, at least or up to about 11 -fold, at least or up to about 12-fold, at least or up to about 13 -fold, at least or up to about 14-fold, at least or up to about 15-fold, at least or up to about 16-fold, at least or up to about 17-fold, at least or up to about 18-fold, at least or up to about 19-fold, at least or up to about 20-fold, at least or up to about 25-fold, at least or up to about 30-fold, at least or up to about 35-fold, at least or up to about 40-fold, at least or up to about
• a compound of the invention can be used, for example, to induce apoptosis, cell cycle arrest, or senescence in a cell.
• the cell is a cancer cell.
• the cell carries a mutation in p53.
• Non-limiting examples of compounds of the invention include compounds of any of the following formulae:
• a compound of the invention is a compound of the formula
• X is CR , N, or NR ; wherein at least one of X 1 , X X 3 , and X 4 is a carbon atom connected to Q 1 ;
• m is 1, 2, 3, or 4;
• Y is N, O, or absent;
• R 1 is -C(0)R 16 , -C(0)OR 16 , -C(0)NR 16 R 17 , - OR 16 , -SR 16 , -NR 16 R 17 , -NR 16 C(0)R 16 , -OC(0)R 16 , -SiR 16 R 17 R 18 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently
• each R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 is independently -C(0)R 21 , -C(0)OR 21 , -C(0)NR 21 R 22 , -OR 21 , -SR 21 , -NR 21 R 22 , - NR 21 C(0)R 22 , -OC(0)R 21 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen; each R 19 and R 20 is C(0)R 23 ,
• the pattern of dashed bonds is chosen to provide an aromatic system, for example, an indole, an indolene, a pyrrolopyridine, a pyrrolopyrimidine, or a pyrrolopyrazine.
• X 1 is CR 5 , CR 5 R 6 , or a carbon atom connected to Q 1 .
• X 2 is CR 7 , CR 7 R 8 , or a carbon atom connected to Q 1 .
• X 3 is CR 9 , CR 9 R 10 , or a carbon atom connected to Q 1 .
• X 4 is CR 11 ,
• X is CR , N, or R .
• X 1 is a carbon atom connected to Q 1 .
• X 2 is a carbon atom connected to Q 1 .
• X 3 is a carbon atom connected to Q 1 .
• X 4 is a carbon atom connected to Q 1 .
• X 5 is N.
• the compound is of the formula:
• the com ound is of the formula:
• m is 1, 2, 3, or 4. In some embodiments, m is 1. In some embodiments, X 3 is carbon atom connected to Q 1 , and m is 1. In some embodiments, the comp nd is of the formula:
• R 1 is alkyl, alkenyl, -C(0)R 16 , -C(0)OR 16 , or -C(0)NR 16 R 17 . In some embodiments, R 1 is a substituted alkyl.
• R 1 can be substituted by one or more substituents selected from hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, cyclic alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, urethane groups, and ester groups.
• R 1 is alkyl substituted with an amine group.
• R 1 is alkyl substituted with R
• Q 1 is alkylene, alkenylene, or alkynylene.
• Q 1 is Ci-alkylene.
• each R 16 and R 17 is independently alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, or hydrogen.
• Q 1 is Ci-alkylene, R 16 is aryl, and R 17 is alkyl.
• Q 1 is Ci-alkylene, R 16 is aryl, and R 17 is hydrogen. In some embodiments, Q 1 is Ci-alkylene, R 16 is heteroaryl, and R 17 is alkyl. In some embodiments, Q 1 is Ci-alkylene, R 16 is heteroaryl, and R 17 is hydrogen. In some embodiments,
• Q 1 is Ci-alkylene, R 16 is substituted heteroaryl, and R 17 is hydrogen.
• Q 1 is Ci-alkylene, R 16 is substituted alkyl, and R 17 is hydrogen.
• R 17 is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted with halogen, alkyl, or hydroxyl.
• R 16 is hydrogen, and R 17 is aryl or heteroaryl, substituted or unsubstituted with halogen or alkyl.
• R 16 is alkyl, and R 17 is heteroaryl substituted with halogen or alkyl.
• R 17 is aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted with alkyl. In some embodiments, R 17 is aryl or heteroaryl, each of which is independently substituted with alkyl, wherein the alkyl is optionally substituted with fluorine, chlorine, bromine, iodine, or cyano.
• R 2 is hydrogen or alkyl.
• R 13 is alkyl, alkenyl, hydrogen, or halogen.
• R 2 is alkyl, and R 13 is alkyl.
• R 2 is hydrogen, and R 13 is alkyl.
• R 2 is methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.
• R 13 is methyl, ethyl, propyl, iso-propyl, butyl or tert-butyl.
• R 2 is hydrogen, and R 13 is hydrogen.
• R 3 is -C(0)R 19 , -C(0)OR 19 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen
• R 4 is -C(0)R 19 , -C(0)OR 19 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen.
• R 3 is hydrogen and R 4 is substituted alkyl.
• R 3 is hydrogen and R 4 is alkyl substituted with aryl.
• R 3 is alkyl and R 4 is alkyl.
• R 3 is alkyl and R 4 is aryl.
• R 3 is hydrogen, and R 4 is heterocyclyl. In some embodiments,
• R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are bound form a ring, wherein the ring is substituted or unsubstituted. In some embodiments, R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are bound form a substituted heterocycle. In some embodiments, R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are bound form a heterocycle substituted with a hydroxyl group, halogen, amino group, or alkyl group. In some embodiments, R 3 and R 4 together with the nitrogen atom to which R 3 and R 4 are bound form a heterocycle, wherein the heterocycle is substituted by a substituted or unsubstituted heterocycle.
• R 3 and R 4 to ether with the nitro en atom to which R 3 and R 4
• R 16 is alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, or hydrogen
• R 17 is aryl, heteroaryl, or heterocyclyl.
• R 17 is phenyl, indolyl, piperidinyl, imidazolyl, thiazolyl, morpholinyl, pyrrolyl, or pyridinyl.
• the compound is of the formula:
• the compound is of the formula
• the compound is of the formula
• each Z 1 and Z 2 is independently CR X or N; each R x is independently -
• each R and R , z 2 o 6 is independently - C(0)R 21 , -C(0)OR 21 , -C(0) R 21 R 22 , -OR 21 , -SR 21 , -S0 2 R 21 , - R 21 R 22 , - R 21 C(0)R 22 , - OC(0)R 21 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, hydrogen, or halogen; each R and R , z 2 o 6 is independently - C(0)R 21 , -C(0)OR 21 , -C(0) R 21 R 22 , -OR 21 , -SR 21 , -S0 2 R 21 , - R 21 R 22 , - R 21 C(0)R 22 , - OC(0)R 21 , alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocycly
• Z 1 is N. In some embodiments, Z 1 and Z 2 are N. In some embodiments, each R 25 and R 26 is independently a halogen. In some embodiments, R 25 is In some embodiments, R 25 is S0 2 R 21 . In some embodiments, R 25 is S0 2 R 21 , wherein
• R Zi is alkyl. In some embodiments, R is S0 2 R , wherein R is methyl.
• Non-limiting examples of compounds of the current disclosure include the following:
• the compound is of the formula
• each L 1 and L 2 is independently an ester, ether, thioether, polyethyleneglycol (PEG), alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocyclylene, arylene, heteroarylene, or heterocycloalkylene group, any of which is substituted or unsubstituted.
• each L 1 and L 2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, or heterocy cl oalky 1 ene .
• L 1 is alkylene and L 2 is an ester.
• Compounds herein can include all stereoisomers, enantiomers, diastereomers, mixtures, racemates, atropisomers, and tautomers thereof.
• Non-limiting examples of optional substituents include hydroxyl groups, sulfhydryl groups, halogens, amino groups, nitro groups, nitroso groups, cyano groups, azido groups, sulfoxide groups, sulfone groups, sulfonamide groups, carboxyl groups, carboxaldehyde groups, imine groups, alkyl groups, halo-alkyl groups, alkenyl groups, halo-alkenyl groups, alkynyl groups, halo-alkynyl groups, alkoxy groups, aryl groups, aryloxy groups, aralkyl groups, arylalkoxy groups, heterocyclyl groups, acyl groups, acyloxy groups, carbamate groups, amide groups, ureido groups, epoxy groups, and ester groups.
• Non-limiting examples of alkyl and alkylene groups include straight, branched, and cyclic alkyl and alkylene groups.
• An alkyl or alkylene group can be, for example, a Ci, C 2 , C 3 , C 4 , C5, C 6 , C 7 , C 8 , C9, Cio, C11, C12, Ci3, Ci4, C15, Ci 6 , C 17 , C 18 , C19, C 20 , C 21 , C 22 , C 23 ,
• Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
• Branched alkyl groups include any straight alkyl group substituted with any number of alkyl groups.
• Non-limiting examples of branched alkyl groups include isopropyl, isobutyl, sec-butyl, and t-butyl.
• Non-limiting examples of substituted alkyl groups includes hydroxymethyl, chloromethyl, trifluorom ethyl, aminom ethyl, 1-chloroethyl, 2-hydroxy ethyl, 1,2- difluoroethyl, and 3-carboxypropyl.
• Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-systems. A cyclic alkyl group can be substituted with any number of straight, branched, or cyclic alkyl groups.
• Non-limiting examples of cyclic alkyl groups include cyclopropyl, 2-methyl- cycloprop-l-yl, cycloprop-2-en-l-yl, cyclobutyl, 2,3-dihydroxycyclobut-l-yl, cyclobut-2-en- 1-yl, cyclopentyl, cyclopent-2-en-l-yl, cyclopenta-2,4-dien-l-yl, cyclohexyl, cyclohex-2-en- 1-yl, cycloheptyl, cyclooctanyl, 2,5-dimethylcyclopent-l-yl, 3,5-dichlorocyclohex-l-yl, 4- hydroxycyclohex-l-yl, 3,3,5-trimethylcyclohex-l-yl, octahydropentalenyl, octahydro-lH- indenyl, 3a,4,5,6,7,7a-
• alkenyl and alkenylene groups include straight, branched, and cyclic alkenyl groups.
• the olefin or olefins of an alkenyl group can be, for example, E, Z, cis, trans, terminal, or exo-methylene.
• An alkenyl or alkenylene group can be, for example, a
• alkenyl and alkenylene groups include ethenyl, prop-l-en-l-yl, isopropenyl, but- l-en-4-yl; 2-chloroethenyl, 4-hydroxybuten-l-yl, 7-hydroxy-7-methyloct-4-en-2-yl, and 7- hy droxy-7-methyloct-3 , 5 -dien-2-yl .
• Non-limiting examples of alkynyl or alkynylene groups include straight, branched, and cyclic alkynyl groups.
• the triple bond of an alkylnyl or alkynylene group can be internal or terminal.
• An alkylnyl or alkynylene group can be, for example, a C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C9, Cio, C11, C12, Ci3, Ci4, Ci5, Ci6, Ci7, Ci 8 , Ci9, C20, C21, C22, C23, C24, C25, C26, C27, C2 8 ,
• alkynyl or alkynylene groups include ethynyl, prop-2-yn-l-yl, prop-l-yn-l-yl, and 2-methyl-hex-4-yn-l- yl; 5-hydroxy-5-methylhex-3-yn-l-yl, 6-hydroxy-6-methylhept-3-yn-2-yl, and 5-hydroxy-5- ethylhept-3 -yn- 1 -yl .
• a halo-alkyl group can be any alkyl group substituted with any number of halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
• a halo-alkenyl group can be any alkenyl group substituted with any number of halogen atoms.
• a halo-alkynyl group can be any alkynyl group substituted with any number of halogen atoms.
• An alkoxy group can be, for example, an oxygen atom substituted with any alkyl, alkenyl, or alkynyl group.
• An ether or an ether group comprises an alkoxy group.
• alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
• An aryl group can be heterocyclic or non-heterocyclic.
• An aryl group can be monocyclic or polycyclic.
• An aryl group can be substituted with any number of substituents described herein, for example, hydrocarbyl groups, alkyl groups, alkoxy groups, and halogen atoms.
• Non-limiting examples of aryl groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and furyl.
• Non-limiting examples of substituted aryl groups include 3,4-dimethylphenyl, 4-tert-butylphenyl, 4-cyclopropylphenyl, 4-diethylaminophenyl, 4-(trifluoromethyl)phenyl, 4-(difluoromethoxy)-phenyl, 4-(trifluoromethoxy)phenyl, 3- chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 2-chlorophenyl, 2- iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3 -fluorophenyl, 3-methylphenyl, 3 -methoxy phenyl, 4-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl,
• Non-limiting examples of substituted aryl groups include 2-aminophenyl, 2-(N- methylamino)phenyl, 2-(N,N-dimethylamino)phenyl, 2-(N-ethylamino)phenyl, 2-(N,N- diethylamino)phenyl, 3-aminophenyl, 3-(N-methylamino)phenyl, 3-(N,N- dimethylamino)phenyl, 3-(N-ethylamino)phenyl, 3-(N,N-diethylamino)phenyl, 4- aminophenyl, 4-(N-methylamino)phenyl, 4-(N,N-dimethylamino)phenyl, 4-(N- ethylamino)phenyl, and 4-(N,N-diethylamino)phenyl.
• a heterocycle can be any ring containing a ring atom that is not carbon, for example, N, O, S, P, Si, B, or any other heteroatom.
• a heterocycle can be substituted with any number of substituents, for example, alkyl groups and halogen atoms.
• a heterocycle can be aromatic (heteroaryl) or non-aromatic.
• Non-limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine, succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran, pyran, and tetrahydropyran.
• Non-limiting examples of heterocycles include: heterocyclic units having a single ring containing one or more heteroatoms, non-limiting examples of which include, diazirinyl, aziridinyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, thiazolidinyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl, 2,3,4,5-tetrahydro-lH-azepinyl, 2,3-dihydro-lH-indole, and 1,2,3,4- tetrahydro
• heteroaryl include: i) heteroaryl rings containing a single ring, non-limiting examples of which include, 1,2,3,4-tetrazolyl, [l,2,3]triazolyl,
• [l,2,4]triazolyl triazinyl, thiazolyl, lH-imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, thiophenyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4- dimethylaminopyridinyl; and ii) heteroaryl rings containing 2 or more fused rings one of which is a heteroaryl ring, non-limiting examples of which include: 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2- ⁇ i]pyrimidinyl, 7H-pyrrolo[2,3- ⁇ i]pyrimidinyl, pyrido[2,3-ii]pyrimidinyl, 4,5,6,7-tetrahydro-l-H-indolyl, quinoxal
• a compound herein can be least 1% pure, at least 2% pure, at least 3% pure, at least 4% pure, at least 5% pure, at least 6% pure, at least 7% pure, at least 8% pure, at least 9% pure, at least 10% pure, at least 11% pure, at least 12% pure, at least 13% pure, at least 14% pure, at least 15% pure, at least 16% pure, at least 17% pure, at least 18% pure, at least 19% pure, at least 20% pure, at least 21% pure, at least 22% pure, at least 23% pure, at least 24% pure, at least 25% pure, at least 26% pure, at least 27% pure, at least 28% pure, at least 29% pure, at least 30% pure, at least 31% pure, at least 32% pure, at least 33% pure, at least 34% pure, at least 35% pure, at least 36% pure, at least 37% pure, at least 38% pure, at least 39% pure, at least 40% pure, at least 4
• compounds of the invention can be used to treat cancer in a subject.
• a compound of the invention can, for example, slow the proliferation of cancer cell lines, or kill cancer cells.
• Non-limiting examples of cancer that can be treated by a compound of the invention include: acute lymphoblastic leukemia, acute myeloid leukemia,
• adrenocortical carcinoma AIDS-related cancers, AIDS-related lymphoma, anal cancer, appendix cancer, astrocytomas, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas, Burkitt lymphoma, carcinoma of unknown primary origin, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, desmoplastic small round cell tumor, endometrial cancer, ependymom
• osteosarcoma/malignant fibrous histiocytoma of bone ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer, pancreatic cancer islet cell, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pituitary adenoma,
• pleuropulmonary blastoma pleuropulmonary blastoma, plasma cell neoplasia, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas, skin cancers, skin carcinoma merkel cell, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, T-cell lymphoma, throat cancer, thymoma, thymic carcinoma, thyroid cancer, trophoblastic tumor (gestational), cancers of unknown primary site, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumor.
• the compounds of the invention show non-lethal toxicity.
• compositions include, for example, acid- addition salts and base-addition salts.
• the acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid.
• a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
• a pharmaceutically-acceptable salt is a metal salt.
• a pharmaceutically-acceptable salt is an ammonium salt.
• Metal salts can arise from the addition of an inorganic base to a compound of the invention.
• the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
• the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
• the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
• a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
• Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the invention.
• the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine, or pipyrazine.
• an ammonium salt is a triethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N- ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, or a pipyrazine salt.
• Acid addition salts can arise from the addition of an acid to a compound of the invention.
• the acid is organic.
• the acid is inorganic.
• the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.
• the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate (mesylate) salt, an ethanesulfonate salt, a benzenesulfonate salt, a p-tolu
• compositions of the invention are provided.
• a pharmaceutical composition of the invention can be used, for example, before, during, or after treatment of a subject with, for example, another pharmaceutical agent.
• Subjects can be, for example, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, neonates, and non-human animals.
• a subject is a patient.
• a pharmaceutical composition of the invention can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
• the pharmaceutical composition facilitates administration of the compound to an organism.
• Pharmaceutical compositions can be administered in therapeutically-effective amounts as pharmaceutical compositions by various forms and routes including, for example, intravenous, subcutaneous, intramuscular, oral, parenteral, ophthalmic, subcutaneous, transdermal, nasal, vaginal, and topical administration.
• a pharmaceutical composition can be administered in a local manner, for example, via injection of the compound directly into an organ, optionally in a depot or sustained release formulation or implant.
• Pharmaceutical compositions can be provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.
• a rapid release form can provide an immediate release.
• An extended release formulation can provide a controlled release or a sustained delayed release.
• compositions can be formulated by combining the active compounds with pharmaceutically-acceptable carriers or excipients.
• Such carriers can be used to formulate liquids, gels, syrups, elixirs, slurries, or suspensions, for oral ingestion by a subject.
• Non-limiting examples of solvents used in an oral dissolvable formulation can include water, ethanol, isopropanol, saline, physiological saline, DMSO, dimethylformamide, potassium phosphate buffer, phosphate buffer saline (PBS), sodium phosphate buffer, 4-2-hydroxyethyl-l-piperazineethanesulfonic acid buffer (HEPES), 3-(N- morpholino)propanesulfonic acid buffer (MOPS), piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), and saline sodium citrate buffer (SSC).
• Non-limiting examples of co-solvents used in an oral dissolvable formulation can include sucrose, urea, cremaphor, DMSO, and potassium phosphate buffer.
• compositions can be formulated for intravenous administration.
• the pharmaceutical compositions can be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Suspensions of the active compounds can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
• the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• the active compounds can be administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams, and ointments.
• Such pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
• the compounds of the invention can be applied topically to the skin, or a body cavity, for example, oral, vaginal, bladder, cranial, spinal, thoracic, or pelvic cavity of a subject.
• the compounds of the invention can be applied to an accessible body cavity.
• the compounds can also be formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, and PEG.
• rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas
• conventional suppository bases such as cocoa butter or other glycerides
• synthetic polymers such as polyvinylpyrrolidone, and PEG.
• a low-melting wax such as a mixture of fatty acid glycerides, optionally in combination with cocoa butter, can be melted.
• therapeutically- effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
• the subject is a mammal such as a human.
• a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
• the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
• compositions can be formulated using one or more physiologically- acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations that can be used pharmaceutically. Formulations can be modified depending upon the route of administration chosen.
• Pharmaceutical compositions comprising a compound described herein can be manufactured, for example, by mixing, dissolving, emulsifying, encapsulating, entrapping, or compression processes.
• compositions can include at least one pharmaceutically- acceptable carrier, diluent, or excipient and compounds described herein as free-base or pharmaceutically-acceptable salt form.
• Pharmaceutical compositions can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
• compositions comprising the compounds described herein include formulating the compounds with one or more inert, pharmaceutically- acceptable excipients or carriers to form a solid, semi-solid, or liquid composition.
• Solid compositions include, for example, powders, tablets, dispersible granules, capsules, and cachets.
• Liquid compositions include, for example, solutions in which a compound is dissolved, emulsions comprising a compound, or a solution containing liposomes, micelles, or nanoparticles comprising a compound as disclosed herein.
• Semi-solid compositions include, for example, gels, suspensions and creams.
• compositions can be in liquid solutions or suspensions, solid forms suitable for solution or suspension in a liquid prior to use, or as emulsions. These compositions can also contain minor amounts of nontoxic, auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically-acceptable additives.
• Non-limiting examples of dosage forms suitable for use in the invention include liquid, powder, gel, nanosuspension, nanoparticle, microgel, aqueous or oily suspensions, emulsion, and any combination thereof.
• Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the invention include binding agents, disintegrating agents, anti-adherents, anti-static agents, surfactants, anti-oxidants, coating agents, coloring agents, plasticizers, preservatives, suspending agents, emulsifying agents, anti-microbial agents, spheronization agents, and any combination thereof.
• a composition of the invention can be, for example, an immediate release form or a controlled release formulation.
• An immediate release formulation can be formulated to allow the compounds to act rapidly.
• Non-limiting examples of immediate release formulations include readily dissolvable formulations.
• a controlled release formulation can be a pharmaceutical formulation that has been adapted such that release rates and release profiles of the active agent can be matched to physiological and chronotherapeutic requirements or, alternatively, has been formulated to effect release of an active agent at a programmed rate.
• controlled release formulations include granules, delayed release granules, hydrogels (e.g., of synthetic or natural origin), other gelling agents (e.g., gel- forming dietary fibers), matrix-based formulations (e.g., formulations comprising a polymeric material having at least one active ingredient dispersed through), granules within a matrix, polymeric mixtures, and granular masses.
• a controlled release formulation is a delayed release form.
• a delayed release form can be formulated to delay a compound' s action for an extended period of time.
• a delayed release form can be formulated to delay the release of an effective dose of one or more compounds, for example, for about 4, about 8, about 12, about 16, or about 24 hours.
• a controlled release formulation can be a sustained release form.
• a sustained release form can be formulated to sustain, for example, the compound' s action over an extended period of time.
• a sustained release form can be formulated to provide an effective dose of any compound described herein (e.g., provide a physiologically-effective blood profile) over about 4, about 8, about 12, about 16 or about 24 hours.
• Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &
• Multiple therapeutic agents can be administered in any order or simultaneously.
• a compound of the invention is administered in combination with, before, or after treatment with another therapeutic agent.
• the multiple therapeutic agents can be provided in a single, unified form, or in multiple forms, for example, as multiple separate pills.
• the agents can be packed together or separately, in a single package or in a plurality of packages.
• One or all of the therapeutic agents can be given in multiple doses. If not simultaneous, the timing between the multiple doses can vary to as much as about a month.
• compositions described herein can be administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a therapeutic agent can vary.
• the compositions can be used as a prophylactic and can be administered continuously to subjects with a propensity to conditions or diseases in order to lessen a likelihood of the occurrence of the disease or condition.
• the compositions can be administered to a subject during or as soon as possible after the onset of the symptoms.
• the administration of the therapeutic agents can be initiated within the first 48 hours of the onset of the symptoms, within the first 24 hours of the onset of the symptoms, within the first 6 hours of the onset of the symptoms, or within 3 hours of the onset of the symptoms.
• the initial administration can be via any route practical, such as by any route described herein using any formulation described herein.
• a compound can be administered as soon as is practical after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from about 1 month to about 3 months.
• the length of time a compound can be administered can be about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 2 months, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 3 months, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 4 months, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 5 months, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 13 months, about 14 months, about 15 months, about 20 weeks, about
• compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
• the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
• the unit dosage can be in the form of a package containing discrete quantities of the formulation.
• Non- limiting examples are packaged injectables, vials, or ampoules.
• Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with or without a
• Formulations for injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
• compositions provided herein can be administered in conjunction with other therapies, for example, chemotherapy, radiation, surgery, anti-inflammatory agents, and selected vitamins.
• the other agents can be administered prior to, after, or concomitantly with the pharmaceutical compositions.
• the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, or gels, for example, in unit dosage form suitable for single administration of a precise dosage.
• nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate.
• Non-limiting examples of pharmaceutically active agents suitable for combination with compositions of the disclosure include anti-infectives, i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.
• anti-infectives i.e., aminoglycosides, antiviral agents, antimicrobials, anticholinergics/antispasmotics, antidiabetic agents, antihypertensive agents, antineoplastics, cardiovascular agents, central nervous system agents, coagulation modifiers, hormones, immunologic agents, immunosuppressive agents, and ophthalmic preparations.
• Liposomes are composed of natural phospholipids, and can contain mixed lipid chains with surfactant properties (e.g., egg phosphatidylethanolamine).
• a liposome design can employ surface ligands for attaching to unhealthy tissue.
• Non-limiting examples of liposomes include the multilamellar vesicle (MLV), the small unilamellar vesicle (SUV), and the large unilamellar vesicle (LUV).
• Liposomal physicochemical properties can be modulated to optimize penetration through biological barriers and retention at the site of administration, and to reduce a likelihood of developing premature degradation and toxicity to non-target tissues.
• Optimal liposomal properties depend on the administration route: large-sized liposomes show good retention upon local injection, small-sized liposomes are better suited to achieve passive targeting.
• PEGylation reduces the uptake of the liposomes by the liver and spleen, and increases the circulation time, resulting in increased localization at the inflamed site due to the enhanced permeability and retention (EPR) effect.
• liposomal surfaces can be modified to achieve selective delivery of the encapsulated drug to specific target cells.
• Non-limiting examples of targeting ligands include monoclonal antibodies, vitamins, peptides, and polysaccharides specific for receptors concentrated on the surface of cells associated with the disease.
• Non-limiting examples of dosage forms suitable for use in the disclosure include liquid, elixir, nanosuspension, aqueous or oily suspensions, drops, syrups, and any combination thereof.
• Non-limiting examples of pharmaceutically-acceptable excipients suitable for use in the disclosure include granulating agents, binding agents, lubricating agents, disintegrating agents, sweetening agents, glidants, anti-adherents, anti-static agents, surfactants, anti-oxidants, gums, coating agents, coloring agents, flavoring agents, coating agents, plasticizers, preservatives, suspending agents, emulsifying agents, plant cellulosic material and spheronization agents, and any combination thereof.
• compositions of the invention can be packaged as a kit.
• a kit includes written instructions on the administration/use of the composition.
• the written material can be, for example, a label.
• the written material can suggest conditions methods of administration.
• the instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
• the written material can be a label.
• the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.
• FDA U.S. Food and Drug Administration
• EMA European Medicines Agency
• compositions described herein can be in unit dosage forms suitable for single administration of precise dosages.
• the formulation is divided into unit doses containing appropriate quantities of one or more compounds.
• the unit dosage can be in the form of a package containing discrete quantities of the formulation.
• Non- limiting examples are liquids in vials or ampoules.
• Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Multiple-dose reclosable containers can be used, for example, in combination with a preservative.
• Formulations for parenteral injection can be presented in unit dosage form, for example, in ampoules, or in multi-dose containers with a preservative.
• a compound described herein can be present in a composition in a range of from about 1 mg to about 2000 mg; from about 100 mg to about 2000 mg; from about 10 mg to about 2000 mg; from about 5 mg to about 1000 mg, from about 10 mg to about 500 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 1 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 300 mg to about 350 mg, from about 350 mg to about 400 mg, from about 400 mg to about 450 mg, from about 450 mg to about 500 mg, from about 500 mg to about 550 mg, from about 550 mg to about 600 mg, from about 600 mg to about 650 mg, from about 650 mg to about 700 mg, from about 700 mg to about 750 mg, from about 750 mg to about 800 mg, from about 800 mg to about 850 mg, from about 850 mg to about 900
• a compound described herein can be present in a composition in an amount of about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about
• a dose can be expressed in terms of an amount of the drug divided by the mass of the subject, for example, milligrams of drug per kilograms of subject body mass.
• a compound is administered in an amount ranging from about 5 mg/kg to about 50 mg/kg, 250 mg/kg to about 2000 mg/kg, about 10 mg/kg to about 800 mg/kg, about 50 mg/kg to about 400 mg/kg, about 100 mg/kg to about 300 mg/kg, or about 150 mg/kg to about 200 mg/kg.
• reaction mixture was stirred at 0 °C for 0.5 h and allowed for warm to 17 °C for 15 h.
• the residue was poured into saturated ammonium chloride solution (1000 mL) and stirred for 3 min.
• the aqueous phase was extracted with ethyl acetate (3 x 500 mL).
• the combined organic phases were washed with brine (2 x 500 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo.
• N-[3-(5-bromo-l-ethyl-indol-2-yl)prop-2-ynyl]-4-fluoro-aniline 700 mg, 1.89 mmol, 1 eq.
• tetrahydrofuran 5.00 mL
• n- butyllithium 2.5 M, 3.02 mL, 4 eq.
• morpholine-4-carbaldehyde (1.09 g, 9.43 mmol, 944 iL, 5 eq.) was added.
• l-Ethyl-2-[3-(4-chloroanilino)prop-l-ynyl]indole-5-carbaldehyde was prepared in a manner similar to that described in Example 6 for the preparation of l-ethyl-2-[3-(4- fluoroanilino)prop-l-ynyl]indole-5-carbaldehyde.
• l-Ethyl-2- ⁇ 3-[(6-methylpyridin-3-yl)amino]prop-l-yn-l-yl ⁇ -lH-indole-5- carbaldehyde was prepared in a manner similar to that described in Example 6 for the preparation of l-ethyl-2-[3-(4-fluoroanilino)prop-l-ynyl]indole-5-carbaldehyde.
• l-Ethyl-2- ⁇ 3-[(6-methylpyridin-3-yl)amino]prop-l-yn-l-yl ⁇ -lH-indole-5- carbaldehyde was prepared in a manner similar to that described in Example 6 for the preparation of l-ethyl-2-[3-(4-fluoroanilino)prop-l-ynyl]indole-5-carbaldehyde.
• l-Ethyl-2- ⁇ 3-[(2-methylpyridin-4-yl)amino]prop-l-yn-l-yl ⁇ -lH-indole-5- carbaldehyde was prepared in a manner similar to that described in Example 6 for the preparation of l-ethyl-2-[3-(4-fluoroanilino)prop-l-ynyl]indole-5-carbaldehyde.
• l-Ethyl-2- ⁇ 3-[(2-methylpyridin-4-yl)amino]prop-l-yn-l-yl ⁇ -lH-indole-5- carbaldehyde was prepared in a manner similar to that described in Example 6 for the preparation of l-ethyl-2-[3-(4-fluoroanilino)prop-l-ynyl]indole-5-carbaldehyde.
• Example 16 Preparation of N-[3-(l-Ethyl-5- ⁇ [(2-methoxyethyl)amino]methyl ⁇ -lH- indol-2-yl)prop-2-yn-l-yl]aniline [0147]
• 2-(3-anilino-l-propynyl)- l-ethyl-lH-indole-5-carbaldehyde was reacted with 2-methoxyethylamine to give N-[3-(l- ethyl-5- ⁇ [(2-methoxyethyl)amino]methyl ⁇ -lH-indol-2-yl)prop-2-yn-l-yl]aniline.
• reaction mixture was poured into a solution of EDTA (20 mL) and stirred for 2 h.
• the mixture was extracted with ethyl acetate (20 mL), and the organic phase was washed by water (50 mL), and brine (50 mL), and dried over anhydrous sodium sulfate.
• the solids were filtered off, and the filtrate was concentrated in vacuo to give the crude product as black brown oil.
• Example 28 Preparation of N- ⁇ [l-(2-Chloroethyl)-2- ⁇ 3-[(4-chlorophenyl)amino]prop-l- yn-l-yl ⁇ -lH-indol-5-yl]methyl ⁇ oxan-4-amine
• Aqueous EDTA solution (20 mL) was added, and the mixture was stirred for 2 h.
• the mixture was extracted with methylene chloride (3 x 10 mL).
• the combined organic layers were washed with water (3 x 10 mL) and brine (10 mL), and dried over anhydrous sodium sulphate. The solids were filtered off, and the filtrate was concentrated in vacuo.
• N-2-propynyl(4-chloro- 3-fluorophenyl)amine was used to prepare N-[(2- ⁇ 3-[(4-chloro-3-fluorophenyl)amino]prop-l- yn- 1 -yl ⁇ - 1 -ethyl- lH-indol-5-yl)methyl]- 1 -methylpiperidin-4-amine.
• the reaction mixture was stirred at 0 °C for 2 h then quenched by saturated solution of sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (2 x 30 mL), and the combined organic phases were washed by water (30 mL), and brine (30 mL), and dried over anhydrous sodium sulfate. The solids were filtered off, and the filtrate was concentrated in vacuo to give a crude residue.
• N-2-propynyl[6-(/ert- butyl)-3-pyridyl]amine was used to prepare 6-tert-butyl-N-[3-(l-ethyl-5- ⁇ [(l- methanesulfonylpiperidin-4-yl)amino]methyl ⁇ -lH-indol-2-yl)prop-2-yn-l-yl]pyridin-3- amine.
• the ester was then saponified by sodium hydroxide in methanol and water to give 2-(4- ⁇ [3 -( 1 -ethyl-5 - ⁇ [( 1 -methylpiperidin-4-yl)amino]methyl ⁇ - 1 H-indol-2-yl)prop-2- yn-l-yl]amino ⁇ phenyl)-2-methylpropanoic acid.
• N-2-propynyl(p- tolyl)amine was used to prepare N-[(l-ethyl-2- ⁇ 3-[(4-methylphenyl)amino]prop-l-yn-l-yl ⁇ - lH-indol-5-yl)methyl]-l-methylpiperidin-4-amine.
• the aqueous phase was extracted with methylene chloride (3 x 5 mL).
• the combined organic phases were washed with brine (3 x 5 mL) and dried over anhydrous sodium sulphate. The solids were filtered off, and the filtrate was concentrated in vacuo.
• Example 45 Preparation of l-(4- ⁇ [(2- ⁇ 3-[(4-Chlorophenyl)amino]prop-l-yn-l-yl ⁇ -l- ethyl-lH-indol-5-yl)methyl]amino ⁇ piperidin-l-yl)ethan-l-one
• N-2-propynyl[p- (trifluoromethyl)phenyl]amine was used to prepare N-(3- ⁇ l-ethyl-5-[(methylamino)methyl]- lH-indol-2-yl ⁇ prop-2-yn-l-yl)-4-(trifluoromethyl)aniline.
• Example 48 Preparation of N-[(l-Ethyl-2- ⁇ 3-[(4-methylphenyl)amino]prop-l-yn-l-yl ⁇ - lH-indol-5-yl)methyl]oxan-4-amine
• N-2-propynyl(p- tolyl)amine was used to prepare N-[(l-ethyl-2- ⁇ 3-[(4-methylphenyl)amino]prop-l-yn-l-yl ⁇ - 1 H-indol-5 -yl)methyl] oxan-4-amine .
• the reaction was diluted with ethyl acetate (50 mL) and EDTA (2M, 100 mL), and the biphasic mixture was stirred at 25 °C for 3 h.
• the reaction mixture was extracted with ethyl acetate (3 x 40 mL). The organic extracts were washed with saturated brine (150 mL) and dried over anhydrous sodium sulphate. The solids were filtered off, and the filtrate was concentrated in vacuo.
• Example 52 Preparation of l-[(2- ⁇ 3-[(4-chlorophenyl)amino]prop-l-yn-l-yl ⁇ -l-ethyl- lH-indol-4-yl)methyl]piperidin-4-ol
• Example 54 Preparation of l-[(2- ⁇ 3-[(4-chlorophenyl)amino]prop-l-yn-l-yl ⁇ -l-ethyl- lH-indol-4-yl)methyl]-N,N-dimethylpiperidin-4-amine
• Example 56 Preparation of l- ⁇ l-[(2- ⁇ 3-[(4-Chlorophenyl)amino]prop-l-yn-l-yl ⁇ -l- ethyl-lH-indol-4-yl)methyl]piperidin-4-yl ⁇ piperidin-4-ol
• Example 57 Preparation of 2-(5- ⁇ [3-(4- ⁇ [4-(4-Aminopiperidin-l-yl)piperidin-l- yl]methyl ⁇ -l-ethyl-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• Example 58 Preparation of l-[(l-ethyl-2- ⁇ 3-[(4-fluorophenyl)amino]prop-l-yn-l-yl ⁇ - lH-indol-5-yl)methyl]-N, -dimethylpiperidin-4-amine
• Example 65 Preparation of 4- ⁇ [3-(l-ethyl-5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -lH-indol-2- yl)prop-2-yn-l-yl]amino ⁇ benzonitrile
• Example 66 Preparation of N-[(2- ⁇ 3-[(4-chloro-3-fluorophenyl)amino]prop-l-yn-l-yl ⁇ - l-ethyl-lH-indol-5-yl)methyl]oxan-4-amine
• Example 70 Preparation of N-[(2- ⁇ 3-[(4-chlorophenyl)amino]prop-l-yn-l-yl ⁇ -l-ethyl- lH-indol-5-yl)methyl]- -(2-methanesulfonylethyl)piperidin-4-amine
• Example 72 Preparation of 2-(4- ⁇ [(2- ⁇ 3-[(4-chlorophenyl)amino]prop-l-yn-l-yl ⁇ -l- ethyl-lH-indol-5-yl)methyl]amino ⁇ piperidin-l-yl)-N,N-dimethylacetamide
• Example 74 Preparation of 2-methyl-2-(5- ⁇ [3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)propanenitrile
• Example 75 Preparation of 2-[5-( ⁇ 3-[l-(2-fluoroethyl)-5- ⁇ [(oxan-4-yl)amino]methyl ⁇ - lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2-yl]-2-methylpropanenitrile
• Example 77 Preparation of 2-[5-( ⁇ 3-[l-(2-chloroethyl)-5- ⁇ [(oxan-4-yl)amino]methyl ⁇ - lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2-yl]-2-methylpropanenitrile
• Example 78 Preparation of 2-[5-( ⁇ 3-[l-(2,2-difluoroethyl)-5- ⁇ [(oxan-4- yl)amino]methyl ⁇ -lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2-yl]-2- methylpropanenitrile
• Example 80 Preparation of ferf-butyl N-( ⁇ 3-ethyl-2-[3-(phenylamino)prop-l-yn-l-yl]- lH-indol-6-yl ⁇ methyl)-N-(oxan-4-yl)carbamate
• N-prop-2-yn-l-yl-aniline (20 mg, 150 ⁇ ) in DMSO (1 mL) was added N-isopropylpropan-2-amine (53 ⁇ , 375 ⁇ ) and copper(I) iodide (5 mg, 25 ⁇ ) at room temperature under nitrogen, with stirring for 5 min.
• Example 83 Preparation of 2-[5-( ⁇ 3-[l-(2-chloroethyl)-5- ⁇ [(l-methylpiperidin-4- yl)amino]methyl ⁇ -lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2-yl]-2- methylpropanenitrile
• Example 86 Preparation of N-( ⁇ 3-ethyl-2-[3-(phenylamino)prop-l-yn-l-yl]-lH-indol-6- yl ⁇ methyl)oxan-4-amine [0243] To the solution of fert-butyl N-( ⁇ 3-ethyl-2-[3-(phenylamino)prop-l-yn-l-yl]-lH- indol-6-yl ⁇ methyl)-N-(oxan-4-yl)carbamate (11 mg, 22.5 ⁇ , prepared as described in Example 80) in acetonitrile (1 mL) was added trichlorobismuthane (50 mg, 158.7 ⁇ , 42.94 ⁇ .), and the reaction mixture was stirred at 50 °C for 25 min.
• trichlorobismuthane 50 mg, 158.7 ⁇ , 42.94 ⁇ .
• Aqueous EDTA solution (20 mL) and ethyl acetate (5 mL) were added, and the mixture was stirred for 2 h.
• the reaction mixture was extracted with ethyl acetate (3 x 10 mL), the combined organic layers were washed with water (3 x 10 mL) and brine (10 mL), and dried over anhydrous magnesium sulphate. The solids were filtered off, and the filtrate was concentrated in vacuo.
• Example 87 Preparation of 2-[5-( ⁇ 3-[l-(2-chloroethyl)-4- ⁇ [4-(pyrrolidin-l-yl)piperidin- l-yl]methyl ⁇ -lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2-yl]-2-methylpropanenitrile
• Example 88 Preparation of 2-(5- ⁇ [3-(5- ⁇ [(l-methanesulfonylpiperidin-4- yl)amino]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-
• Example 91 Preparation of 2- ⁇ 5-[(3- ⁇ 5-[( ⁇ l-[2-(dimethylamino)acetyl]piperidin-4- yl ⁇ amino)methyl]-l-(2,2,2-trifluoroethyl)-lH-indol-2-yl ⁇ prop-2-yn-l-yl)amino]pyridin-
• Example 92 Preparation of 2-methyl-2-(5- ⁇ [3-(5- ⁇ [(l-methylpiperidin-4- yl)amino]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-
• Example 96 Preparation of 2-[5-( ⁇ 3-[l-(cyclopropylmethyl)-5- ⁇ [(oxan-4- yl)amino]methyl ⁇ -lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2-yl]-2- methylpropanenitrile
• Example 99 Preparation of 2-(5- ⁇ [3-(l-ethyl-7-fluoro-4- ⁇ [4-(pyrrolidin-l-yl)piperidin-l- yl]methyl ⁇ -lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2-methylpropanenitrile
• Example 101 Preparation of 2-(5- ⁇ [3-(4- ⁇ [4-(4-hydroxypiperidin-l-yl)piperidin-l- yl]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• Example 102 Preparation of N-(6-cyanopyridin-3-yl)-3-(l-ethyl-5- ⁇ [(l-methylpiperidin- 4-yl)amino]methyl ⁇ -lH-indol-2-yl)prop-2-ynamide [0259] In a manner similar to the method described in Example 28, N-(6-cyanopyridin-3-yl)- 3-(l-ethyl-5- ⁇ [(l-methylpiperidin-4-yl)amino]methyl ⁇ -lH-indol-2-yl)prop-2-ynamide was prepared.
• Example 103 Preparation of N-[6-(l-cyano-l-methylethyl)pyridin-3-yl]-3-(5- ⁇ [(oxan-4- yl)amino]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-ynamide
• Example 104 Preparation of N-[6-(l-cyano-l-methylethyl)pyridin-3-yl]-3-(5- ⁇ [(l- methylpiperidin-4-yl)amino]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2- ynamide
• Example 105 Preparation of 2-methyl-2-(5- ⁇ [3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l- (oxiran-2-ylmethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)propanenitrile
• Example 106 Preparation of 2-(5- ⁇ [3-(5- ⁇ [(2-methoxyethyl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• Example 107 Preparation of 2-methyl-2-[5-( ⁇ 3-[5-( ⁇ [2-(morpholin-4- yl)ethyl]amino ⁇ methyl)-l-(2,2,2-trifluoroethyl)-lH-indol-2-yl]prop-2-yn-l- yl ⁇ amino)pyridin-2-yl]propanenitrile
• Example 108 Preparation of 2-methyl-2-(5- ⁇ [3-(4- ⁇ [(l-methylpiperidin-4- yl)amino]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-
• Example 109 Preparation of 2-methyl-2-(5- ⁇ [3-(4- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)propanenitrile
• Example 111 Preparation of 2-(5- ⁇ [3-(7-fluoro-4- ⁇ [4-(pyrrolidin-l-yl)piperidin-l- yl]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• Example 112 Preparation of 2-methyl-2-[5-( ⁇ 3-[l-(2,2,2-trifluoroethyl)-5- ⁇ [(2,2,2- trifluoroethyl)amino]methyl ⁇ -lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2- yljpropanenitrile
• Example 113 Preparation of 2-[5-( ⁇ 3-[5-( ⁇ [l-(2-hydroxyethyl)piperidin-4- yl]amino ⁇ methyl)-l-(2,2,2-trifluoroethyl)-lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-
• Example 114 Preparation of 2-[5-( ⁇ 3-[5-( ⁇ [l-(2-methoxyethyl)piperidin-4- yl]amino ⁇ methyl)-l-(2,2,2-trifluoroethyl)-lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino
• Example 117 Preparation of 2-(5- ⁇ [3-(4- ⁇ [(2-methoxyethyl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• Example 119 Preparation of 2- ⁇ 5-[(3- ⁇ 4-[(4-acetylpiperazin-l-yl)methyl]-l-(2,2,2- trifluoroethyl)-lH-indol-2-yl ⁇ prop-2-yn-l-yl)amino]pyridin-2-yl ⁇ -2- methylpropanenitrile
• Example 122 Preparation of 2-[5-( ⁇ 3-[4-(hydroxymethyl)-l-(2,2,2-trifluoroethyl)-lH- indol-2-yl] prop-2-yn- 1-yl ⁇ amino)pyridin-2-yl] -2-methylpropanenitrile
• Example 123 Preparation of 2-methyl-2-[5-( ⁇ 3-[4-( ⁇ 4-[2-(morpholin-4-yl)-2- oxoethyl]piperazin-l-yl ⁇ methyl)-l-(2,2,2-trifluoroethyl)-lH-indol-2-yl]prop-2-yn-l- yl ⁇ amino)pyridin-2-yl]propanenitrile
• Example 125 Preparation of methyl 5- ⁇ [3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridine-2-carboxylate
• Example 128 Preparation of N-(2-methoxyethyl)-5- ⁇ [3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ - l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridine-2-carboxamide
• Example 129 Preparation of 2-[(5- ⁇ [3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)formamido]acetic acid
• Example 131 Preparation of N-(2-methanesulfonylethyl)-5- ⁇ [3-(5- ⁇ [(oxan-4- yl)amino]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridine-
• Example 132 Preparation of 2-[5-( ⁇ 3-[l-(cyanomethyl)-5- ⁇ [(oxan-4-yl)amino]methyl ⁇ - lH-indol-2-yl]prop-2-yn- -yl ⁇ amino)pyridin-2-yl]-2-methylpropanenitrile
• Example 133 Preparation of 2-methyl-2-[5-( ⁇ 3-[l-(2-methylpropyl)-5- ⁇ [(oxan-4- yl)amino]methyl ⁇ -lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2-yl]propanenitrile
• Example 134 Preparation of 2-methyl-2- ⁇ 5-[(3- ⁇ 4-[(oxan-4-yl)amino]-l-(2,2,2- trifluoroethyl)-lH-indol-2-yl ⁇ prop-2-yn-l-yl)amino]pyridin-2-yl ⁇ propanenitrile
• Example 138 Preparation of 2-teri-butyl-N-[3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]pyrimidin-5-amine
• Example 141 Preparation of 2-(5- ⁇ [3-(7-chloro-4- ⁇ [4-(pyrrolidin-l-yl)piperidin-l- yl]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• Example 142 Preparation of 2-(5- ⁇ [3-(6-fluoro-4- ⁇ [4-(pyrrolidin-l-yl)piperidin-l- yl]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• the crude material was purified by flash column chromatography (ISCO 20g, eluting with a gradient of ethyl acetate and hexanes). The desired fractions were eluted with 50% ethyl acetate in hexanes. The fractions were combined to give 2-(5- ⁇ 3-[4-bromo-7-fluoro-l-(2,2,2- trifluoroethyl)-lH-indol-2-yl]-2-propynylamino ⁇ -2-pyridyl)-2-methylpropiononitrile (120 mg, 41% yield).
• the reaction mixture was heated at 65 C under a nitrogen atmosphere for 10 h.
• 0.5 M EDTA (4 mL) and ethyl acetate (10 mL) were added to the reaction mixture, which was stirred at room temperature for 1 h.
• the organic phases were extracted with ethyl acetate (2x).
• the combined organic phases were washed with brine (3x), dried over anhydrous sodium sulfate, then concentrated.
• the crude material was purified by flash column chromatography (ISCO 12g, eluting with a gradient of ethyl acetate and hexanes) to give the recovered starting material (60 mg) and the desired 2-(5- ⁇ 3-[7-fluoro-4-formyl-l-(2,2,2-trifluoroethyl)-lH-indol-2-yl]-2- propynylamino ⁇ -2-pyridyl)-2-methylpropiononitrile (40 mg, 75% yield based on starting material recovery), as the more polar compound.
• Example 143 Preparation of 2-(5- ⁇ [3-(l-ethyl-5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -lH- pyrrolo[2,3-c]pyridin-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2-methylpropanenitrile
• Example 144 Preparation of 2-methyl-2-(5- ⁇ [3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-pyrrolo[2,3-c]pyridin-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2- yl)propanenitrile
• Example 146 Preparation of 2-(5- ⁇ [3-(7-chloro-4- ⁇ [4-(pyrrolidin-l-yl)piperidin-l- yl]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-pyrrolo[2,3-c]pyridin-2-yl)prop-2-yn-l- yl]amino ⁇ pyridin-2-yl)-2-methylpropanenitrile
• the aqueous phase was extracted with ethyl acetate (3 x 150 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated.
• the crude product was purified by flash column chromatography (silica gel, eluting with a 1/1 mixture of ethyl acetate and petroleum ether) to afford 4-bromo-7-chloro-lH-pyrrolo[2,3-c]pyridine as a yellow solid (4.12 g, 21% yield).
• ammonium chloride 50 mL at 0 °C.
• Example 166 Preparation of 2-methyl-2-[5-( ⁇ 3-[l-(oxiran-2-ylmethyl)-4- ⁇ [4-(pyrrolidin- l-yl)piperidin-l-yl]methyl ⁇ -lH-indol-2-yl]prop-2-yn-l-yl ⁇ amino)pyridin-2- yl]propanenitrile
• Example 168 Preparation of 2-methyl-2-(5- ⁇ [3-(6- ⁇ [(oxan-4-yl)amino]methyl ⁇ -3-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)propanenitrile
• Example 170 Preparation of 2-(5- ⁇ [3-(3-ethyl-6- ⁇ [(l-methylpiperidin-4- yl)amino]methyl ⁇ -lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• the crude product was purified by flash column chromatography (silica gel, eluting with methylene chloride/methanol: 100/1) to give fert-butyl-N-(6-chloro- 1 - ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ - lH-indol-4-yl)-N-(l - methylpiperidin-4-yl)carbamate as yellow oil (1.20 g, 2.31 mmol, 65% yield, 95% purity).
• Example 173 Preparation of 2-(3- ⁇ [6-(l-cyano-l-methylethyl)pyridin-3-yl]amino ⁇ prop- l-yn-l-yl)-6-fluoro-N-(l-methylpiperidin-4-yl)-l-(2,2,2-trifluoroethyl)-lH-indole-4- carboxamide
• Example 142 in tetrahydrofuran (4 mL) and water (1 mL) was added 2-methylbut-2-ene (388 mg, 5.54 mmol), NaH 2 P0 4 (133 mg, 1.1 1 mmol), and NaC10 2 (400 mg, 4.43 mmol, added in several small portions). The resulting reaction mixture was stirred at 25 °C for 1 h, poured into 30 mL aqueous ammonium chloride, and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), brine (10 mL), and dried over anhydrous sodium sulfate, and concentrated.
• l-methylpiperidin-4-amine (20 mg, 174.52 ⁇ ) was added to the reaction mixture.
• the resulting reaction mixture was stirred at 25 °C for 30 min, poured into 30 mL of aqueous ammonium chloride, and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (3 x 10 mL), brine (10 mL), dried over anhydrous sodium sulfate, and concentrated.
• Example 175 Preparation of 6-fluoro-2- ⁇ 3-[(6-methanesulfonylpyridin-3- yl)amino]prop-l-yn-l-yl ⁇ -N-(l-methylpiperidin-4-yl)-l-(2,2,2-trifluoroethyl)-lH-indol-
• Example 172 6-fluoro-2- ⁇ 3 -[(6-methanesulfonylpyridin-3 -yl)amino]prop- 1 -yn- 1 -yl ⁇ -N-( 1 - methylpiperidin-4-yl)-l -(2,2,2-trifluoroethyl)- lH-indol-4-amine was prepared.
• Example 177 Preparation of 5-[(3- ⁇ 6-fluoro-4-[(l-methylpiperidin-4-yl)amino]-l-(2,2,2- trifluoroethyl)-lH-indol-2-yl ⁇ prop-2-yn-l-yl)amino]-N-(pyridin-3-yl)pyridine-2- carboxamide
• Example 178 Preparation of 2-methyl-2-(5- ⁇ [3-(5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-pyrrolo[2,3-b]pyridin-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2- yl)propanenitrile
• Example 179 Preparation of 2-methyl-2- ⁇ 5-[(3- ⁇ 4-[(l-methylpiperidin-4-yl)amino]-l- (2,2,2-trifluoroethyl)-lH-pyrrolo[2,3-b]pyridin-2-yl ⁇ prop-2-yn-l-yl)amino]pyridin-2- yljpropanenitrile
• tetrakis(triphenylphosphine)palladium(0) 44 mg, 38.11 ⁇
• the reaction was stirred at 25 °C for 2 h under a nitrogen atmosphere, and poured into water (5 mL).
• the reaction mixture was extracted with ethyl acetate (3 x 20 mL), and the combined organic layers were stirred with saturated ethylenediamine-tetraacetic acid (EDTA) solution (-20 mL) for 1 h.
• EDTA saturated ethylenediamine-tetraacetic acid
• reaction mixture was stirred at 50 °C for 2 h, and then diluted with water (-10 mL).
• the reaction mixture was extracted with ethyl acetate (3 x 10 mL), and the combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
• Example 180 Preparation of 2-(5- ⁇ [3-(7-chloro-l-ethyl-4- ⁇ [4-(pyrrolidin-l-yl)piperidin- l-yl]methyl ⁇ -lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2-methylpropanenitrile
• Example 181 Preparation of 2-(5- ⁇ [3-(7-chloro-5- ⁇ [(oxan-4-yl)amino]methyl ⁇ -l-(2,2,2- trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-2-yl)-2- methylpropanenitrile
• Example 182 Preparation of 2-(5- ⁇ [3-(7-chloro-5- ⁇ [(l-methylpiperidin-4- yl)amino]methyl ⁇ -l-(2,2,2-trifluoroethyl)-lH-indol-2-yl)prop-2-yn-l-yl]amino ⁇ pyridin-

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